ReviewThe use of mycophenolate mofetil in transplant recipients
Section snippets
Introduction and history
At the beginning of the 1990s, several needs in transplant immunosuppression remained unmet. The advent of cyclosporine (CsA), potent polyclonal anti-lymphocyte antibodies and anti-CD3 antibodies in the early 1980s resulted in improved 1-year graft survival rates. However, acute allograft rejection remained frequent and was a leading cause of graft loss during the first year and a risk factor for the development of chronic rejection and long-term graft loss Palmer et al., 1985, Foegh, 1990,
Mechanisms of action
MPA, a product of a Penicillium fungus, was originally isolated in 1896 (Gosio, 1896), and shown to have anti-neoplastic Williams et al., 1968, Carter et al., 1969, Suzuki et al., 1969, Brewin et al., 1972, anti-viral, anti-fungal (Florey et al., 1946), and immunosuppressive activity (Mitsui and Suzuki, 1969). MMF is the semi-synthetic morpholinoethyl ester of MPA (Fig. 1). After oral administration and absorption of MMF, the ester linkage is rapidly hydrolyzed by esterases to yield MPA, the
Clinical trials
The primary objective for the addition of MMF to maintenance immunosuppression regimens was to reduce the frequency of acute allograft rejection. Investigators also hoped to reduce dependence on the more toxic immunosuppressives (CsA, tacrolimus, steroids) without precipitating acute or chronic rejection, thereby attenuating or preventing the side effects associated with these drugs.
Renal transplantation
MMF was approved by the US Food and Drug Administration for the prevention of acute rejection in renal transplantation in June 1995. Three randomized, double-blinded, controlled trials in renal transplantation demonstrated that MMF is more effective than AZA or placebo in combination with CsA, plus a steroid, for prevention of allograft rejection. However, patient or graft survival at 1 year was not improved by MMF treatment compared to AZA or placebo in any of the studies. MMF has also been
Liver transplantation
With the successful use in kidney transplants, MMF treatment is currently being evaluated in liver transplant recipients. The trend towards improved outcomes such as decreased incidence of acute rejection and increased response to treatment of acute rejection suggest that there may also be applications for MMF in liver transplantation. An additional benefit of adding MMF to tacrolimus-based immunosuppression is the ability to reduce the dose of tacrolimus in an attempt to decrease the
Heart transplantation
Cardiac allograft rejection has many features in common with kidney transplantation including a significant effect of HLA matching, and a significant incidence of chronic deterioration, particularly of the coronary vessels. Thus it is expected that it would respond to the same immunosuppressive strategies, including MMF. However, rejection in heart transplants is usually monitored by histological changes on protocol biopsies rather than by function change which are monitored in renal
Lung transplantation
MMF treatment has been studied in several small, non-randomized studies. Patients treated with MMF had significantly fewer episodes of acute rejection compared to patients receiving AZA. Although several end-points did not reach statistical significance, most likely due to small numbers of patients in the trials, MMF treatment was associated with more effective maintenance of lung function compared to AZA demonstrated by a lower prevalence of obliterative bronchiolitis Ross et al., 1998,
Pancreas or simultaneous kidney/pancreas (SPK) transplantation
Pancreas transplantation has become an accepted treatment option for labile insulin-dependent diabetics in an attempt to promote insulin-independence and/or improve glucose homeostasis. A kidney transplant is often carried out simultaneously (SPK) or subsequent to the pancreas transplant for patients with diabetic nephropathy. Although patients are exchanging insulin-dependence for life-long immunosuppression, patients who have end-stage renal failure secondary to diabetic nephropathy will
Adverse events and toxicity
The majority of data concerning the safety and tolerability of MMF in transplant recipients is derived from the three large clinical trials in renal transplantation and one large heart transplantation trial European Mycophenolate Mofetil Study Group, 1995, US Renal Transplant Mycophenolate Mofetil Study Group and Solinger, 1995, Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group, 1996, Kobashigawa et al., 1998. MMF is generally a well-tolerated drug, lacking permanent organ
Economic considerations
As with any other new treatment modality introduced into clinical use, cost-effectiveness is an important consideration in determining whether MMF will gain widespread use. New drugs pose problems when they impose new add-on costs rather than replacing existing drugs. MMF used with CsA or tacrolimus thus involves two expensive drugs.
To address the economic consequences of MMF treatment, an economic evaluation of MMF for the prevention of acute renal allograft rejection following primary
Conclusions
Although MMF has been most extensively studied in renal transplantation, it has proven to be a useful agent in all solid organ transplantation. MMF has a selective immunosuppressive effect with minimal toxicity and appears to be more effective than AZA. The addition of MMF to CsA- or tacrolimus-based immunosuppression results in decreased acute and recurrent renal allograft rejection episodes. Although the addition of MMF does not affect 1-year patient or graft survival, there is a trend
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